Prognosis of Morbid Obesity Patients With Advanced Heart Failure

Transcription

1 ORIGINAL PAPER Prognosis of Morbid Obesity Patients With Advanced Heart Failure Vijaiganesh Nagarajan, MD, MRCP; 1 Clay A. Cauthen, MD; 2 Randall C. Starling, MD, MPH; 2 Wai Hong Wilson Tang, MD 2 From the Department of Hospital Medicine, Medicine Institute, 1 and Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 2 Obese patients have been noted to have better prognosis in many conditions including heart failure. We hypothesize that this favorable prognosis for obesity may not be seen in patients with morbid obesity and advanced heart failure. A total of 501 consecutive patients with advanced heart failure referred for heart transplant evaluation to the Cleveland Clinic were studied. Patients were categorized into 3 groups based on their body mass index score as nonobese ( 30 kg/m 2 ), obese ( kg/m 2 ), and morbidly obese ( 40 kg/m 2 ). There were fewer cardiovascular risk factors in the morbidly obese group. Unadjusted event-free survival rates were 48.4%, 57.4%, and 28.6% in the nonobese, obese, and morbidly obese groups, respectively (P=.02). In univariate analysis, both the nonobese group (hazard ratio [HR], 1.44; 95% confidence interval [CI], ; P=.01) and the morbidly obese group (HR, 2.46; 95% CI, ; P=.002) had significantly higher risk of all-cause mortality/transplantation compared with the obese group. This difference persisted in multivariate analysis after adjustment for confounding factors. Our study re-emphasizes the presence of an obesity paradox even in patients with very advanced heart failure. This favorable prognosis, however, may not be relevant in patients with morbidly obesity. Cardiovascular risk factors may not contribute to this phenomenon ª2013 Wiley Periodicals, Inc. Address for correspondence: W. H. Wilson Tang, MD, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH tangw@ccf.org Manuscript received: April 1, 2013; revised: May 11, 2013; accepted: May 13, 2013 DOI: /chf Obesity is a growing epidemic and is one of the major public health concerns of the current era. Most epidemiologic studies define obesity based on body mass index (BMI). Recently published data were concerning as they showed that approximately 35% of the US adult population were obese, with a mean BMI of 28.7 kg/m 2. 1 Obesity is defined as a BMI 30 kg/m 2, and severe obesity (BMI 40 kg/m 2 ) is termed morbid or extreme obesity. 2 Obesity has been linked to multiple medical problems including diabetes, hypertension, dyslipidemia, heart failure (HF), atrial fibrillation, and other cardiovascular comorbidities. Recent data suggest that adipose tissue works as a separate organ and affects cardiovascular health by multiple mechanisms such as increased inflammatory markers and increased cardiac output. 3 Obesity has not only been associated with morbidity, but in a very large study using pooled data, it has been clearly associated with increased allcause mortality. 4 In 2002, however, Gruberg and colleagues made an interesting observation they called an obesity paradox. They noted that the mortality rate was significantly lower in obese patients undergoing percutaneous coronary intervention. 5 Similar findings have been noted in many other patient populations, for instance, in patients with cancer, renal failure, and chronic obstructive lung disease. 3 Similar findings were noted in HF patients in a large meta-analysis involving 28,209 patients. 6 Nevertheless, few studies have evaluated prognostic implications of morbid obesity in the HF population. HYPOTHESIS We expected to see the phenomenon of an obesity paradox in our advanced HF population. We also hypothesized that the relatively more favorable prognosis for obesity might diminish in morbidly obese patients with advanced HF in contemporary medical management. METHODS Data Source We used a large database of more than 500 consecutive patients with advanced end-stage HF referred for cardiac transplant evaluation and other advanced HF therapies to a tertiary level reference center between 2007 and Patients underwent comprehensive evaluation in our advanced HF clinic, including laboratory investigations, echocardiography, metabolic stress test, and cardiac catheterization. We used electronic medical records to collect important data, which included demographic information, baseline clinical characteristics, medical history, medications, laboratory test results, and procedures performed. Echocardiographic data were obtained from our echocardiography database. The data were managed by an independent researcher not responsible for care of these patients. Participation in this study did not require any alteration to the medical management of patients. Height and weight were obtained at the time of comprehensive evaluation in our advanced HF clinic, and BMI was calculated from this information. Our retrospective study was approved by the Cleveland Clinic s institutional review board. 160 Vol. 19 No. 4 July. August 2013 Congest Heart Fail. 2013;19:

2 Definitions Patients were categorized into 3 groups based on their BMI using the National Institute of Health s (NIH s) classification of obesity. Patients who were underweight (BMI <18.5 kg/m 2 ) were excluded from the analysis. Patients with normal BMI ( kg/m 2 ) and overweight ( kg/m 2 ) were grouped together in a nonobese group. Patients with BMI between 30 kg/m 2 and 39.9 kg/m 2 were designated as obese. Patients with BMI 40 kg/m 2 were classified as extreme or morbidly obese. The primary outcome of interest was all-cause mortality and/or transplantation, with a maximum follow-up of 3.8 years. We used medical records and the hospital transplantation index to identify both patients and date of transplantation. Statistical Analysis Dichotomous categorical data were reported as percentages, and chi-square test was used to detect differences. Continuous variables were mostly not normally distributed, thus were summarized using medians and compared using the Kruskal-Wallis test. Survival analysis was performed using Kaplan-Meier estimates, and differences between curves were calculated using log-rank statistics (Figure 1). The association between BMI and primary outcome was analyzed using univariate and multivariate Cox proportional hazard models, with the obese group as the reference. Differences with P value <.05 were considered statistically significant. All statistics were performed using SPSS version 19.0 (IBM, Armonk, NY). RESULTS A total of 501 consecutive patients were included for final analysis. The cohort was 74.3% male. The proportion of patients who were nonobese (64%, n=318), obese (32%, n=162), and morbidly obese (4%, n=21) was compatible with that of the general population. 7 Baseline characteristics stratified by BMI groups are shown in the Table 1. Diabetes and hypertension, two important cardiovascular risk factors, were significantly different among the 3 groups. The proportion of diabetes was 20.4%, 37.7%, and 28.6% in nonobese, obese, and morbidly obese groups, respectively. Similarly, the proportion of patient with hypertension was 38.7%, 53.1%, and 42.9% among the 3 groups, respectively. Interestingly, obese patients had the highest proportion of patients with these cardiovascular risk factors. Other risk factors were not significantly different among the 3 groups. In addition, the use of neurohormonal antagonists (b-blockers and angiotensin-converting enzyme [ACE] inhibitors) was lowest in the morbidly obese group (Table 1). Significantly higher creatinine and lower albumin levels have been seen in morbidly obese groups. Overall, this cohort of advanced HF patients had a high mortality/transplant rate (49.5%, n=248), with unadjusted event-free survival rates of 48.4%, 57.4%, and 28.6% in nonobese, obese, and morbidly obese groups, respectively (P=.02). Obese patients had a better survival rate compared with both nonobese and morbidly obese groups (log-rank test, P=.002). In univariate analysis, both the nonobese group (hazard FIGURE 1. Kaplan-Meier curves showing better survival of obese patients compared with nonobese patients (obesity paradox) and also worst survival rates of morbidly obese patients (reversal of obesity paradox). Log-rank test Congest Heart Fail Vol. 19 No. 4 July. August

3 TABLE 1. Baseline Characteristics Nonobese (n=318) Obese (n=162) Morbidly Obese (n=21) P Value Age, median (IQR), y 57 (49 64) 55 (46 62) 56 (39 63).01 Men, % Weight, median (IQR), lb 165 ( ) 222 ( ) 326 ( ).001 Diabetes, % Hypertension, % Dyslipidemia, % COPD, % CAD, % CVA/TIA, % Smoking, % Atrial fibrillation, % Systolic BP, median (IQR), mm Hg 106 (95 121) 107 ( ) 109 ( ).223 Diastolic BP, median (IQR), mm Hg 72 (65 81) 73 (66 80) 76 (73 81).079 Aspirin, % Clopidogrel, % b-blockers, % ACE inhibitors, % Spironolactone, % Hydralazine, % Nitrates, % ARB, % Sodium, median (IQR), mm 136 ( ) 136 ( ) 136 ( ).28 Creatinine, median (IQR), mg/dl 1.19 ( ) 1.19 ( ) 1.39 ( ).001 Albumin, median (IQR), g/dl 3.9 ( ) 4.0 ( ) 3.6 ( ).002 Troponin, median (IQR), ng/ml 0.12 ( ) 0.12 ( ) 0.23 ( ).87 BNP, median (IQR), pg/ml 560 ( ) 301 ( ) 639 ( ).001 Blood urea nitrogen, median (IQR), mg/dl 23 (17 33) 23 (17 33) 25 (16 35).59 RDW, median (IQR) 15.8 ( ) 15.1 ( ) 15.3 ( ).004 Bold P values indicate significance. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; BP, blood pressure; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CVA/TIA, cerebrovascular accident/ transient ischemic attack; IQR, interquartile range; red cell distribution width. ratio [HR], 1.44; 95% confidence interval [CI], ; P=.01) and the morbidly obese group (HR, 2.46; 95% CI, ; P=.002) had significantly higher risk of all-cause mortality/transplantation compared with that of the obese group. In multivariate analysis, after adjustment for diabetes mellitus, hypertension, b-blockers, ACE inhibitors, creatinine, albumin, and BNP, the non-obese (HR, 1.76; 95% CI, ; P=.021) and morbidly obese groups (HR, 2.98; 95% CI, ; P=.007) were associated with higher risk of mortality compared with the obese group. The only other significant variable in this multivariate analysis was albumin (P=.007). There was no correlation between BMI and pulmonary artery pressures (data not shown). DISCUSSION Overall, our results demonstrated that even in patients with very advanced HF, obese patients had a more favorable outcome then nonobese patients. Similar findings have been seen in other studies as well. 8,9 As described earlier, a large meta-analysis involving 28,209 HF patients re-emphasized that overweight and obese patients had lower all-cause and cardiovascular mortality. 6 Another study analyzed 108,927 patients with acute decompensated HF and found that higher BMI is associated with lower in-hospital mortality. 10 This phenomenon of obesity paradox was not only seen in HF patients, but also in patients with multiple other cardiac and noncardiac medical conditions. 11,12 Multiple theories have been proposed to explain this phenomenon, although none of them could explain all its aspects. Advanced HF is recognized as a cachectic disease. One popular theory claims that high metabolic reserve in obese patients may help tolerate the catabolic effects of HF, 13 as cardiac cachexia has long been associated with poor prognosis. 14 Other possibilities such as decreased sympathetic drive and attenuated neurohormonal response have also been suggested. 15 Also, lower B-type natriuretic peptide (BNP) levels have been noted in obese patients. In our patient population, although obese patients had lower BNP, morbidly obese patients had very high BNP, which could represent a sicker patient population. Our study differs from other studies in a few important aspects. First, our patient population was comprised of patients with end-stage HF referred for cardiac transplant evaluation and other advanced HF therapies to our tertiary level reference center. Second, all of our patients underwent comprehensive 162 Congest Heart Fail Vol. 19 No. 4 July. August 2013

4 transplant evaluation including extensive laboratory investigations, cardiac imaging, and invasive investigations. Many of the large epidemiological studies did not have the benefit of such detailed information. Another key finding of our study is that the obesity paradox may not be readily applicable to morbidly obese patients. In the general population, a possible U-shaped relationship between BMI and mortality has been observed. 16 Similar findings have been noted in other disease conditions including acute myocardial infarction. 17,18 Few data exist on the prognosis of HF patients with morbid obesity (BMI 40 kg/m 2 ). Even in the few available studies, clinical outcomes associated with morbidly obese patients with HF vary depending on the cohorts studied. In large clinical trials, a mild increase in mortality among ambulatory patients with mild to moderate HF and BMI 35 has been observed, albeit not statistically significant. 19 In contrast, observational series have not noted increased mortality in patients with very high BMI. 20 Hence, our observation calls into question whether the obesity paradox extends to the morbidly obese in the setting of HF. The association of morbid obesity and mortality was thought to be secondary to cardiovascular risk factors. 21 However, in our cohort, there were two interesting findings. First, prevalence of diabetes and hypertension was highest in the obese group with lowest mortality. Hence, there was no clear relationship between cardiovascular risk factors and observed rate of mortality. Second, use of b-blockers and ACE inhibitors was highest among obese patients and lowest among morbidly obese patients in our cohort. As use of b-blockers and ACE inhibitors has been shown to have mortality benefit in multiple trials, this could be a contributing factor for some of our study findings. Obesity-related nephropathy may also play a role in the findings as morbidly obese patients had a slightly higher creatinine level than other groups (1.39 vs 1.19 mg/dl). Furthermore, higher BNP levels were observed in the morbidly obese group, which may, in part, also be caused by renal insufficiency, 25 as BNP levels tend to be lower in obese patients. 26 In addition, albumin levels were slightly lower in the morbidly obese group, but nutritional deficiencies are not uncommon in such patients. 27 However, morbid obesity still portends poorer outcomes compared with obesity even after adjusting for all these variables. Patients with a BMI 35 were noted to have a 46% lower likelihood of receiving heart transplantation while on the waiting list, which may play a role in this finding as well. 28 STUDY STRENGTHS AND LIMITATIONS The principal limitation of this study is the small number of patients with morbid obesity; however, it is comparable to the proportion of morbidly obese patients in the general population. 7 Nevertheless, because of the very high mortality rate observed in our sickest group of HF patients, we can demonstrate statistical significance. While this study may not be used to draw conclusions, we believe it should prompt an investigation into similar findings in larger registries. Currently, multiple studies are evaluating alternative indices of nutritional status and obesity other than BMI, looking for a better index than BMI. A recently published study from Lavie and colleagues 29 suggested that cardiorespiratory fitness should be taken into consideration when the obesity paradox is considered. Despite the retrospective nature of our study and the lack of objective assessment of nutritional status, our single-center experience provides one of the largest reported series with outcome measures and careful covariate adjustments in patients with advanced HF and morbid obesity. Limited data exist on the benefit of intentional weight loss in patients with advanced HF. As improvement in cardiac performance and symptomatic status has been noted in patients who undergo bariatric surgery, 30 further studies are therefore warranted to justify weight loss and bariatric surgery in morbidly obese patients with HF despite a perceived obesity paradox. CONCLUSIONS Our study re-emphasizes the presence of an obesity paradox even in very advanced HF patients, yet it may not be relevant in patients who are morbidly obese. 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